Adenovirus-mediated p16 transfer to glioma cells induces G1 arrest and protects from paclitaxel and topotecan: implications for therapy.
Malignant gliomas are highly resistant to chemotherapy, in part because of the blood-brain barrier, which restricts the delivery of chemotherapy to certain areas of tumor and their cellular heterogeneity, which leads to the selection and propagation of resistant clones. However, the molecular basis of the drug resistance is poorly understood. In this study, we examined the effect of the cell cycle-inhibitory protein p16 on the chemosensitivity of human glioma cells. Treatment of the p16-null glioma cells, U-251 MG and D-54 MG, with paclitaxel and topotecan, resulted in cell death within 4 days. However, overexpression of exogenous wild-type p16 protein using an adenovirus vector resulted in G1 arrest of glioma cells and resistance to the anticancer effect of paclitaxel or topotecan. Specifically, the p16-expressing cells showed a 30-fold increase in the ID50 of topotecan and a more than 40-fold increase in the ID50 of paclitaxel. These observations indicate that overexpression of molecules that control cell-cycle progression may be partially responsible for causing the resistance of glioma cells to cytocidal drugs.
Fueyo
J
J
Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, Box 316, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Gomez-Manzano
C
C
Puduvalli
V K
VK
Martin-Duque
P
P
Perez-Soler
R
R
Levin
V A
VA
Yung
W K
WK
Kyritsis
A P
AP
D000256:Adenoviridae; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D016193:G1 Phase; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D017239:Paclitaxel / Q000627:therapeutic use / Q000633:toxicity*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013997:Time Factors; D019772:Topotecan / Q000627:therapeutic use / Q000633:toxicity*; D014162:Transfection
D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011994:Recombinant Proteins; D019772:Topotecan; D017239:Paclitaxel